State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, PR China.
Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
Eur J Med Chem. 2021 Jan 1;209:112913. doi: 10.1016/j.ejmech.2020.112913. Epub 2020 Oct 21.
In various human cancers, PI3Ks pathway is ubiquitously dysregulated and thus become a promising anti-cancer target. To discover new potent and selective PI3K inhibitors as potential anticancer drugs, new pyrrolo[2,1-f][1,2,4]triazines were designed, leading to the discovery of compound 37 (CYH33), a selective PI3Kα inhibitor (IC = 5.9 nM, β/α, δ/α,γ/α = 101-, 13-, 38-fold). Western blot analysis confirmed that compound 37 could inhibit phosphorylation of AKT in human cancer cells to modulate the cellular PI3K/AKT/mTOR pathway. And further evaluation in vivo against SKOV-3 xenograft models demonstrated that a dose-dependent antitumor efficacy was achieved.
在各种人类癌症中，PI3Ks 通路普遍失调，因此成为有前途的抗癌靶点。为了发现新的有效和选择性的 PI3K 抑制剂作为潜在的抗癌药物，设计了新的吡咯并[2,1-f][1,2,4]三嗪，发现了化合物 37（CYH33），一种选择性的 PI3Kα 抑制剂（IC=5.9 nM，β/α、δ/α、γ/α=101、13、38 倍）。Western blot 分析证实，化合物 37 能够抑制人癌细胞中 AKT 的磷酸化，从而调节细胞内的 PI3K/AKT/mTOR 通路。进一步在 SKOV-3 异种移植模型中的体内评估表明，实现了剂量依赖性的抗肿瘤疗效。
